SUMMARY

• Guselkumab is a human monoclonal immunoglobulin G1λ (IgG1λ) antibody that selectively binds to the p19 subunit of interleukin 23 (IL-23) and inhibits its interaction with the IL-23 receptor. IL-23 is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Guselkumab inhibits the release of proinflammatory cytokines and chemokines.¹
• The mean half-life (T_1/2) of guselkumab was approximately 15-18 days in subjects with plaque psoriasis (PsO) across trials.¹
• A phase 1, 2-part, randomized, double-blind, placebo-controlled, first-in-human, singleascending-dose study of TREMFYA concluded that the mean maximum serum concentration (C_max) and area under the zero-to-infinity serum concentration-time curve (AUC_0∞) of guselkumab increased in an approximately dose-proportional manner over the dose range of 0.03-10 mg/kg following a single intravenous (IV) administration or that of 10300 mg following a single subcutaneous (SC) administration.²
• Using pooled data from two phase 3 trials (DISCOVER-1 and DISCOVER-2), population pharmacokinetic (PK) modeling analyses and exposure-response modeling analyses were conducted to describe the PK of SC TREMFYA, quantify the effects of intrinsic or extrinsic factors on PK variability, and characterize the relationship between guselkumab exposure and clinical efficacy measures in adult patients with active psoriatic arthritis (PsA) receiving SC TREMFYA therapy.³
  • In a landmark analysis, the baseline Disease Activity Score in 28 joints (DAS28) was identified as a covariate that affected the maximum drug effect (E_max) for the 3 exposure-response models of the American College of Rheumatology (ACR) response that used different exposure metrics (area under the curve [AUC] from weeks 024 [AUC_0-24wk], average concentration at steady state [C_ave,ss], and trough serum concentration [C_trough] at week 20 [C_trough,wk20]). Patients with lower baseline DAS28 scores were predicted to achieve higher maximum 20%, 50%, and 70% improvement in ACR response criteria (ACR20, ACR50, and ACR70, respectively) relative to baseline.
  • A longitudinal model predicted that a higher baseline Psoriasis Area and Severity Index (PASI) score and/or C-reactive protein (CRP) level would be associated with a lower half-maximum drug effect (EC₅₀) and a slightly higher probability of achieving an ACR20, ACR50, and ACR70 response.
• A PK analysis across 9 clinical studies, including a phase 1 study in healthy subjects and multiple phase 2 and 3 studies in different patient populations (PsO, PsA, and palmoplantar pustulosis [PPP]), developed a comprehensive population PK model for guselkumab. Covariates that explained intersubject variability were identified, and relationships between covariates were assessed.⁴
  • For guselkumab, the model-estimated clearance (CL) was 0.255 L/d, central (Vc) and peripheral (Vp) volumes were 3.60 L and 1.78 L, respectively, absorption rate constant (Ka) was 0.313 d^-1, and mean absolute bioavailability was 49.2%.
  • Body weight was the primary factor affecting CL and Vc.

Company core data sheet

Clinical Pharmacology

Mechanism of Action

Guselkumab is a human IgG1λ monoclonal antibody (mAb) that binds selectively to the IL-23) protein with high specificity and affinity. IL-23, a regulatory cytokine, affects the differentiation, expansion, and survival of T cell subsets, (eg, T helper 17 [Th17] cells and Tc17 cells) and innate immune cell subsets, which represent sources of effector cytokines, including IL-17A, IL-17F and IL-22 that drive inflammatory disease. In humans, selective blockade of IL-23 was shown to normalize production of these cytokines.¹

Levels of IL-23 are elevated in the skin of patients with plaque PsO. In in vitro models, guselkumab was shown to inhibit the bioactivity of IL-23 by blocking its interaction with cell surface IL-23 receptor, disrupting IL-23-mediated signaling, activation and cytokine cascades. Guselkumab exerts clinical effects in plaque PsO and PsA through blockade of the IL-23 cytokine pathway.¹

Pharmacodynamic Effects

In a Phase 1 study, treatment with guselkumab resulted in reduced expression of IL-23/Th17 pathway genes and PsO-associated gene expression profiles, as shown by analyses of messenger RNA (mRNA) obtained from lesional skin biopsies of psoriatic subjects at week 12 compared to baseline. In the same Phase 1 study, treatment with guselkumab resulted in improvement of histological measures of PsO at week 12, including reductions in epidermal thickness and T-cell density. In addition, reduced serum IL-17A,
IL-17F and IL-22 levels compared to placebo were observed in guselkumab-treated subjects in Phase 2 and Phase 3 studies in plaque PsO. These results are consistent with the clinical benefit observed with guselkumab treatment in plaque PsO.¹

In Phase 3 studies in PsA, evaluated subjects had elevated serum levels of acute phase proteins CRP, serum amyloid A and IL-6, and Th17 effector cytokines IL-17A, IL-17F and IL-22 at baseline. Guselkumab decreased levels of these proteins within 4 weeks of initiation of treatment. By week 24, guselkumab further reduced the levels of these proteins compared to baseline and also to placebo. In guselkumab-treated subjects, serum IL-17A and IL-17F levels were similar to those observed in a demographically matched healthy cohort at Week 24.¹

PK Properties

Absorption

Following a single 100 mg SC injection in healthy subjects, guselkumab reached a mean (± standard deviation; SD) C_max of 8.09 ± 3.68 mcg/mL by approximately 5.5 days post dose.¹

Steady-state serum guselkumab concentrations were achieved by Week 20 following SC administrations of 100 mg guselkumab at Weeks 0 and 4, and q8w thereafter. The mean (± SD) steady-state guselkumab C_trough values in two Phase 3 studies in plaque PsO were 1.15 ± 0.73 mcg/mL and 1.23 ± 0.84 mcg/mL. Serum guselkumab concentrations did not appear to accumulate over time when given SC q8w.¹

The PK of guselkumab in subjects with PsA was similar to that in subjects with plaque PsO. Following SC administration of 100 mg of guselkumab at Weeks 0, 4, and q8w thereafter, mean steady-state guselkumab C_trough was approximately 1.2 mcg/mL. Following SC administration of 100 mg of guselkumab every 4 weeks (q4w), mean steady-state guselkumab C_trough was approximately 3.8 mcg/mL.¹

The absolute bioavailability of guselkumab following a single 100 mg SC injection was estimated to be approximately 49% in healthy subjects.¹

Distribution

Mean volume of distribution during the terminal phase (Vz) following a single IV administration to healthy subjects ranged from approximately 7-10 L (98-123 mL/kg) across studies.¹

Metabolism

The exact pathway through which guselkumab is metabolized has not been characterized. As a human IgG mAb, guselkumab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.¹

Elimination

Mean systemic CL following a single IV administration to healthy subjects ranged from 0.288 to 0.479 L/day (3.6-6.0 mL/day/kg) across studies.¹

Mean T_1/2 of guselkumab was approximately 17 days in healthy subjects and approximately 15-18 days in subjects with plaque PsO across studies.¹

Dose Linearity

The systemic exposure of guselkumab (C_max and AUC) increased in an approximately dose-proportional manner following a single SC injection at doses ranging from 10 mg to 300 mg in healthy subjects or subjects with plaque PsO.¹

Population PK Analysis

In a population PK analysis, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.516 L/d and 13.5 L, respectively, and the T_1/2 was approximately 18 days in subjects with PsO.¹

In the population PK analysis, the effects of baseline demographics (weight, age, sex, and race), immunogenicity, baseline disease characteristics, comorbidities (past and current history of diabetes, hypertension, and hyperlipidemia), past use of therapeutic biologics, past use of methotrexate or cyclosporine, concomitant medications (nonsteroidal anti-inflammatory drug [NSAIDs], corticosteroids and conventional synthetic disease-modifying antirheumatic drugs [DMARDs] such as methotrexate), use of alcohol, or current smoking status, on PK of guselkumab was evaluated. Only the effects of body weight on CL/F and V/F were found to be significant, with a trend towards higher CL/F in heavier subjects. However, subsequent exposure-response modeling analysis suggested that no dose adjustment would be warranted for body weight.¹

Cytochrome P450 Substrates

An in vitro study using human hepatocytes showed that IL-23 did not alter the expression or activity of multiple cytochrome P450 (CYP450) enzymes (CYP1A2, 2B6, 2C9, 2C19, 2D6, or 3A4).¹

The effects of guselkumab on the PK of representative probe substrates of CYP isozymes (midazolam [CYP3A4], warfarin [CYP2C9], omeprazole [CYP2C19], dextromethorphan [CYP2D6], and caffeine [CYP1A2]) were evaluated in subjects with moderate to severe plaque PsO. Results from this study indicate that changes in C_max and AUC_inf of midazolam, S-warfarin, omeprazole, dextromethorphan, and caffeine after a single dose of guselkumab were not clinically relevant.¹

There is no need for dose adjustment when co-administering guselkumab and CYP450 substrates.¹

CLINICAL DATA

Phase 1 Study

Zhuang et al (2016)² conducted a phase 1, 2-part, randomized, double-blind, placebo-controlled, first-in-human, single-ascending-dose study of TREMFYA.

Study Design/Methods

• In part 1, 2 cohorts comprising of 4 healthy subjects each were randomized (3 active/1 placebo) to receive 0.03- and 0.1 mg/kg IV doses, and 4 cohorts of 8 healthy subjects each were randomized (6 active/2 placebo) to receive
  0.3-, 1-, 3-, and 10 mg/kg IV doses.
• Also in part 1, 7 healthy subjects were randomized (6 active/1 placebo) to receive a single SC dose of TREMFYA 3 mg/kg or placebo.
• In part 2, 4 cohorts of 6 patients each with PsO were randomized (5 active/1 placebo) to receive each SC dose level of TREMFYA (10, 30, 100, and 300 mg) or placebo.
• The TREMFYA doses chosen for the study were based on in vitro bioactivity of guselkumab and guselkumab toxicology and PK findings in cynomolgus monkeys.
• For part 1, healthy male or female subjects, 18-55 years of age (inclusive), who had a body mass index of 18.5-30 kg/m² and weight of 50-100 kg, were eligible for enrollment into the study if no clinically significant abnormalities were observed.
• For part 2, male or female patients who were 18-65 years of age (inclusive) and weighed <130 kg were eligible for enrollment. Patients had plaque-type PsO ≥6 months prior to administration of study agent and covering ≥10% of total body surface area at screening and baseline, as well as a PASI score ≥12 at screening and at the time of administration of study agent.
• The objectives of the study were to assess the PK, safety, and tolerability of guselkumab following a single 30-minute IV infusion or SC administration to healthy subjects (part 1) and following a single SC administration to patients with moderate-to-severe PsO (part 2).

Results

• A total of 47 patients were randomized in part 1, and 24 patients were randomized in part 2.
• Mean C_max and AUC_0-∞ of guselkumab increased in an approximately dose-proportional manner over the dose range of 0.03-10 mg/kg following a single IV administration or that of 10-300 mg following a single SC administration.
• Mean CL and volume of distribution ranged from 3.62 to 6.03 mL/day/kg and
  99.38-123.22 mL/kg, respectively.
• Mean T_1/2 ranged from 12 to 19 days in healthy subjects and patients with PsO.

Population PK Analyses

Chen et al (2022)³ conducted population PK modeling analyses and exposure-response modeling analyses to describe the PK of SC TREMFYA, quantify the effects of intrinsic or extrinsic factors that affect the PK variability, and characterize the relationship between guselkumab exposure and clinical efficacy measures in adult patients with active PsA receiving SC TREMFYA therapy.

Study Design/Methods

• Pooled data from two phase 3, randomized, double-blind, placebo-controlled, multicenter studies, DISCOVER-1 and DISCOVER-2, were used in this study.
  • Patients with active PsA were randomized (1:1:1) to receive TREMFYA 100 mg SC q4w, TREMFYA 100 mg SC at weeks 0 and 4 followed by q8w, or placebo SC q4w.
  • Data through week 24 were used for the population PK and exposure-response modeling analyses.
• Landmark analyses were performed for the ACR responses at weeks 20 (a predose visit for both TREMFYA regimens) and 24 (the primary analysis timepoint).

Results

Patient Characteristics

• Overall, 746, 1120, and 1116 patients were included in the population PK analysis and landmark and longitudinal analyses for exposure-response modeling, respectively.³

Population PK Modeling Analysis

Final Model

• The model parameters were estimated with a percentage relative standard error (%RSE) <17%.
• For a typical population with a median weight of 84 kg, the estimated CL/F was 0.596 L/day, estimated V/F was 15.5 L, and estimated first-order Ka was ~0.572/day.

Simulations

• Concentration-time profiles following the 2 TREMFYA regimens were simulated using the final population PK model to compare covariate subpopulations.
• In patients with a body weight ≥90 kg vs <90 kg, C_trough and AUC during dosing interval (AUCτ) were, respectively, 30.4% and 28.8% lower with the q4w regimen and 33.4% and 28.8% lower with the q8w regimen.
• In patients with vs without diabetes, C_trough and AUCτ were, respectively, 22.6% and 18.9% lower with the q4w regimen and 30.3% and 18.9% lower with the q8w regimen.

Exposure-Response Modeling Analyses

Landmark Analyses

• The baseline DAS28 score was identified as a covariate that affected the E_max for the 3 exposure-response models of ACR response that used different exposure metrics (AUC_0-24wk, C_ave,ss, and C_trough,wk20).
• For the 2 landmark models using different exposure metrics (C_ave,ss and C_trough,wk20), the baseline PASI score was identified as a covariate affecting E_max.
• Investigator’s Global Assessment (IGA) responses correlated with AUC_0-24wk and C_ave,ss.
• Baseline PASI score was the only covariate that had significant effects on both the intercept and E_max.

Longitudinal Modeling

• Observed data showed that patients with median baseline PASI score >5.8 and/or median baseline CRP level >0.94 mg/dL were more sensitive to treatment with TREMFYA and had greater ACR response rates.
• Observed data showed that patients with higher baseline DAS28 scores (>6.1, the population median) had lower ACR response rates.

Simulations

• The final landmark exposure-response models (using the exposure metric C_ave,ss) were used to simulate ACR and IGA responses in order to quantify the differences in ACR and IGA responses with the 2 dose regimens (q4w and q8w) and in different covariate subpopulations.
• For the ACR20, ACR50, and ACR70 response rates at week 24 stratified by baseline DAS28 (≤5.1 vs >5.1) and PASI (≤5.8 vs >5.8) scores and the IGA score of cleared or minimal (IGA 0/1) and IGA score of cleared (IGA 0) responses at week 24 stratified by baseline PASI score (≤5.8 vs >5.8) for the q4w and q8w regimens, see Table: Landmark Exposure-Response Model Simulated ACR20, ACR50, and ACR70 Responses and IGA 0 and IGA 0/1 Responses at Week 24.

Exposure-Safety Analyses

• Safety was not associated with observed or model-predicted exposure metrics, as indicated by the analyses evaluating the relationship between systemic guselkumab exposure and the occurrence of select safety events (ie, adverse events [AEs], serious AEs [SAEs], AEs leading to discontinuation of study agent, infections, and serious infections).

Tran et al (2022)⁴ described the PK of TREMFYA across 9 clinical studies, including a phase 1 study in healthy patients and multiple phase 2 and 3 studies in different patient populations (PsO, PsA, and PPP) using a population PK modeling approach. Covariates that explained intersubject variability were identified and relationships between covariates were assessed.

Study Design/Methods

• For the study designs, population, and PK sampling schemes, see Table: PK Sampling Schemes in the Clinical Studies Included in the Population PK Analysis.

• Data from the studies included in the analysis were combined into a single nonlinear mixed-effects modeling (NONMEM)-ready file for model development.

Results

• Across all studies, median age was 45 (range, 18-82) years.
• The median body weight was 83 (range, 37-203) kg. Patients with PsA, PsO, and PPP and healthy patients had median body weights of 83.5 kg, 87.1 kg, 59.6 kg, and 67.8 kg, respectively.

Final Reduced Model

• For a patient weighing 70 kg, the model-estimated mean CL was 0.255 L/d, mean Vc was 3.60 L and mean Vp was 1.78 L, mean ka was 0.313 d^-1, and mean absolute bioavailability was 49.2%.
  • The terminal T_1/2 was estimated to be approximately 14.6 days.
• The effect of covariates on CL and Vc is summarized in the Table: Effect of Covariates on CL and Vc in the Final Population PK Model.

Simulations

• Median AUC and C_trough of patients weighing <90 kg were 38% and 39% higher, respectively, compared with those weighing ≥90 kg.
• Among patients with PsA, PsO, and PPP, median AUC increased by 9%, 4%, and 31%, respectively, and median C_trough increased by 23%, 15%, and 44%, respectively, compared to healthy patients.
  • AUC and C_trough did not differ by >26.3% between any 2 patient populations, indicating that the type of disease condition did not have any apparent effect on guselkumab PK.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 03 January 2025.